title: Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation.
abstract: BACKGROUND
  A massive destruction of transplanted tissue occurs immediately following transplantation of pancreatic islets from pig to non-human primates. The detrimental instant blood-mediated inflammatory reaction (IBMIR), triggered by the porcine islets, is a likely explanation for this tissue loss. This reaction may also be responsible for mediating an adaptive immune response in the recipient that requires a heavy immunosuppressive regimen.
  
  
  METHODS
  Low molecular weight dextran sulfate (LMW-DS) and the complement inhibitor Compstatin were used in a combination of in vitro and in vivo studies designed to dissect the xenogeneic IBMIR in a non-human primate model of pancreatic islet transplantation. Adult porcine islets (10,000 IEQs/kg) were transplanted intraportally into three pairs of cynomolgus monkeys that had been treated with LMW-DS or heparin (control), and the effects on the IBMIR were characterized. Porcine islets were also incubated in human blood plasma in vitro to assess complement inhibition by LMW-DS and Compstatin.
  
  
  RESULTS
  Morphological scoring and immunohistochemical staining revealed that the severe islet destruction and macrophage, neutrophilic granulocyte, and T-cell infiltration observed in the control (heparin-treated) animals were abrogated in the LMW-DS-treated monkeys. Both coagulation and complement activation were significantly reduced in monkeys treated with LMW-DS, but IgM and complement fragments were still found on the islet surface. This residual complement activation could be inhibited by Compstatin in vitro.
  
  
  CONCLUSIONS
  The xenogeneic IBMIR in this non-human primate model is characterized by an immediate binding of antibodies that triggers deleterious complement activation and a subsequent clotting reaction that leads to further complement activation. The effectiveness of LMW-DS (in vivo and in vitro) and Compstatin (in vitro) in inhibiting this IBMIR provides the basis for a protocol that can be used to abrogate the IBMIR in pig-human clinical islet transplantation.
authors.affiliation: Tohoku University International Advanced Research and Education Organization, Tohoku University, Sendai, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Goto
authors.forename: Jenny
authors.initials: J
authors.lastname: Tjernberg
authors.forename: Denis
authors.initials: D
authors.lastname: Dufrane
authors.forename: Graciela
authors.initials: G
authors.lastname: Elgue
authors.forename: Daniel
authors.initials: D
authors.lastname: Brandhorst
authors.forename: Kristina Nilsson
authors.initials: KN
authors.lastname: Ekdahl
authors.forename: Heidi
authors.initials: H
authors.lastname: Brandhorst
authors.forename: Lars
authors.initials: L
authors.lastname: Wennberg
authors.forename: Yoshimochi
authors.initials: Y
authors.lastname: Kurokawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Satomi
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Pierre
authors.initials: P
authors.lastname: Gianello
authors.forename: Olle
authors.initials: O
authors.lastname: Korsgren
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000008:administration & dosage; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood* / Q000209:etiology*; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008252:Macaca fascicularis; D010456:Peptides, Cyclic / Q000008:administration & dosage; D034421:Sus scrofa; D014183:Transplantation, Heterologous
chemical_list: D016207:Cytokines; D010456:Peptides, Cyclic; C111828:compstatin; D006493:Heparin; D016264:Dextran Sulfate